Primary prevention of Alzheimer's disease (AD) promises great clinical and economic benefits but poses great challenges because the pathologic processes of AD start years or even decades prior to clinical symptoms of dementia. Using cerebrospinal fluid (CSF) AD biomarkers (e.g., total tau [t-tau], tau phosphorylated at threonine 181 [p-tau181] and A[unreadable]42) as clinical trial endpoints offers the potential to demonstrate disease- modifying effects of putative preventive agents in designs with reasonable sample sizes and follow up periods. Simvastatin, a safe and widely used cholesterol-lowering drug, is an attractive candidate preventive agent, as epidemiologic studies from our laboratory and others indicate that statin use is associated with both a reduced risk of clinical AD and reduced neurofibrillary tangle burden at autopsy. In addition, we recently demonstrated that 14 weeks of treatment with simvastatin (which has high central nervous system [CNS] penetration) reduced CSF levels of t-tau and p-tau181 in cognitively normal hypercholesterolemic subjects while treatment with pravastatin (which has low CNS penetration) did not. This pilot study provided valuable "proof-of-concept" evidence that using CSF AD biomarkers as clinical trial endpoints is both safe and feasible. The study proposed here is a 1-year fixed dose, randomized, placebo-controlled trial to evaluate the effects of simvastatin (40 mg/d) vs. placebo on CSF AD biomarkers in middle-aged (45-64 years) cognitively normal subjects (N=50 per group). Primary outcome measures are CSF t-tau, p-tau181, A[unreadable]42 and brain derived neurotropic factor (BDNF). Secondary outcome measures include inflammatory markers (Interleukin [IL]-6, IL-8, S1002), and oxidative stress markers (F2-isoprostanes) and the brain cholesterol metabolite (24S-hydroxycholesterol). Study outcomes and cognitive safety assessments (psychometric measures of simple and sustained attention, working and declarative memory, and complex reasoning) will be measured prior to and at 12 months of treatment. Adverse effects (including serum lipids, liver function tests, and creatine phosphokinase levels) will be monitored at 6-weeks and at 3-, 6-, and 12-months. The findings of the proposed study may provide support for conducting large-scale primary prevention trials in persons at high risk for AD using CSF biomarker as primary outcome measures. PUBLIC HEALTH RELEVANCE: Primary prevention of Alzheimer disease (AD) promises both clinical benefits for patients and their families and substantial economic benefits for society. Delaying the onset of AD by 5 years would reduce the number of AD cases by 50% in a generation, saving billions of health care dollars. Simvastatin has been widely used for prevention of coronary artery disease. The findings of the proposed study may provide proof of concept in support of large scale primary prevention trials in persons at high risk for AD.